Apixaban (INN, trade name Eliquis) is a selective inhibitor of FXa and it is approved by the USFDA for the prevention of venous thromboembolic events (VTE) in adults, who have undergone elective hip or knee replacement surgery.
Apixaban is chemically known as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c]pyridine-3-carboxamide of formula I. The empirical molecular formula is C25H25N5O4. Its molecular weight is 459.5, and its chemical structure is represented below:

Apixaban was first generically disclosed in U.S. Pat. No. 6,413,980 and later it has been specifically disclosed in U.S. Pat. No. 6,967,208. The process for its preparation comprises reacting 4-iodo aniline (VIII) with 5-bromo valeryl chloride to form the compound of formula (VII). The compound of formula (VII) is treated with phosphorous pentachloride and excess morpholine to provide compound of formula (VI), further it is reacted with the compound of formula (V), followed by 8-valerolactam in an Ullmann condensation to get the compound of formula (II). The amidation has been taken place in presence of ethylene glycol and aqueous ammonia to afford the compound of formula (I).
The above synthetic process is illustrated as per the following Scheme-I

WO 2003/049681 discloses a process for the preparation of Apixaban by two synthetic routes. The first synthetic route comprises a reaction of δ-valerolactam (III) with phosphorus pentachloride to provide the compound of formula (IX), which is further reacted with lithium carbonate in DMF followed by morpholine in the presence of triethylamine to produce the compound of formula XI. The compound of formula XI is condensed with the compound of formula (V) to give the compound of formula (XII). The condensation of the compounds of formulas (XII) and (VII) in the presence of potassium carbonate and cuprous iodide as catalyst yields the compound of formula (II), followed by reaction with isobutylchloroformate to form a mixed acid anhydride, which is then transferred with excess ammonia solution to the compound of formula (I).
The above described synthetic process is illustrated as per following Scheme-II

In the second synthetic route disclosed in WO '681, the compound of formula (XIII) is reacted with morpholinein excess to give the compound of formula (VI), which is further treated with δ-valerolactam (III) in the presence of Cs2CO3 and Cu(PPh3)3Br to give the compound of formula (XIV). The compound of formula (XIV) is condensed with the compound of formula (V) to give a compound of formula (II) and followed by the addition of an excess of sodium methoxide and 10 equivalents of formamide to obtain the compound of formula (I).
The above described synthetic process is illustrated as per following Scheme-III

The complex processes for the preparation of the Apixaban and its intermediates, which are known from the prior art, comprise the use of expensive and corrosive/toxic reagents and require drastic reaction conditions. The abovementioned reagents and process conditions—especially those required for preparing the Apixaban intermediate, 3-morpholine-4-yl-1-[4-(2-oxo-piperidin-1-yl)phenyl]-5,6-dihydro-1H-pyridin-2-one of formula (XIV)—are difficult to handle and to apply in industrially scale.
Hence, there is consequently a need for an improved method for the preparation of Apixaban and its intermediates which does not involve the problems described above. Said method particularly should result in less impurities, should be industrially scalable, should allow the desired compounds to be obtained with high yields, should use cheaper reagents which are simpler to handle and eco-friendly, and should also use mild reaction conditions.
The inventors of the present invention have developed an improved process for preparing Apixaban being more eco-friendly as well as cost-effective and providing good yields and an improved purity.